Epidemiology and laboratory investigations suggest that soy, tea and grapes can have beneficial effects on human health, including breast and prostate cancers. Significant components of these foods are the polyphenolic compounds genistein, (-)-epigallocatechin-3-gallate (EGCG) and resveratrol. These compounds were part of the diet of Asians who, following emigration to the United States and adoption of a western diet, lose protection against breast and prostate cancers. In the laboratory, it has been demonstrated that early life (prepubertal) genistein treatment alone programs against chemically-induced mammary cancer in rats. The cellular mechanism of genistein action has been shown to be linked to mammary gland and cell differentiation, thereby identifying potential gene and protein targets of genistein. The goal of this proposal is to investigate the potential of pure polyphenols, alone and in combination, to protect against breast and prostate cancers, with the emphasis on early dietary intervention for programming against mammary and prostate cancers, and to identify the signalling and others pathways by which the polyphenols have their effect. We will test the hypothesis that exposure to combinational polyphenolic nutrients will result in life-time additive or synergistic chemoprotective effects against these cancers. Our specific aims are: A) to investigate the potential of the polyphenols, genistein, EGCG and resveratrol, alone and in combination, to protect against chemically-induced mammary cancer in a rat model and spontaneously developing prostate cancer in a transgenic mouse model (TRAMP); B) to investigate the potential of these polyphenols to enhance mammary and prostate gland maturation and cell differentiation, and to regulate cell proliferation; C) to perform gene expression analyses in mammary glands/epithelial cell preparations of rats and prostates of mice exposed to polyphenols using high-density oligonucleotide-based GeneChips from Affymetrix and spotted oligonucleotide arrays; and D) to identify protein profiles that are differentially expressed in mammary glands of rats and prostate of TRAMP mice treated with polyphenols using proteomics technology. Determination of genes and proteins modulated by nutrient polyphenols at a critical stage of development will identify genetic pathways that play a role in determining cancer susceptibility.